Current Standard of Care of Metastatic Cancer
Metastatic cancers are often fatal, affecting persons of all ages and backgrounds. While great advances in patient care have been realized in recent years by employing novel agents, such as molecular targeted therapies and immune checkpoint inhibitors, the majority of metastatic (Stage IV) cancers are currently incurable. Thus, novel approaches are needed to improve outcomes for patients with metastatic disease, which is refractory to existing therapies.
Rationale for Employing Novel Immunotherapeutic Approaches to Treat Solid Tumors
A strategy for improving treatment of human cancers, is to provoke a robust and targeted cellular immune response against cells expressing tumor-specific antigens and tumor-associated antigens, for example by administration of an immunogenic composition that elicits an immune response targeting the cancer cells. For the purposes of this disclosure, tumor-specific antigens are defined as antigens (specific amino acid sequences) that are exclusively expressed in tumor cells, whereas tumor-associated antigens are defined as antigens, which are putatively expressed only in the organ from which the founder cancer cell originates.
Targeting of Non-Vital Cells Using Tissue Restricted Antigens
While engaging the immune system to eradicate cells expressing tumor-specific antigens offers an exquisitely high therapeutic index whereby only cancer cells are targeted for elimination, eliciting immune-mediated destruction of cells expressing tumor-associated antigens (self-antigens) implies provoking targeted autoimmune disease, and there are inherent risks. In the case of tumor-associated antigens, only antigens present in cells not critical to sustaining life may be safely targeted. Therefore, ubiquitously expressed antigens, or antigens normally expressed in vital organs, such as the brain, liver, kidneys, lungs, immune cells and bone marrow cannot be safely targeted.
However, due to tissue restricted antigen expression, cells expressing certain self-antigens can be targeted with some margin of safety. For instance, the thyroid, ovaries, prostate, and breast tissue all have important functions, but patients can survive without these organs. Additionally, non-synonymous coding mutations, which make cancer cells genetically distinct from their host, also function as viable tumor-specific targets.
Fulfilling an Unmet Clinical Need
In recent years, the field of cancer immunotherapy has witnessed a number of novel approaches to manipulate the host's immune system to eliminate tumor cells. However, tumors displaying a “cold” immunogenic signature, characterized by the absence of infiltrating immune cells are often resistant to immune checkpoint inhibitors, targeting the PD-1 and CTLA-4 axes. Turning “cold” tumors “hot” by priming a vigorous cellular immune response would likely synergize with immune checkpoint inhibitors to be produce durable responses. The present invention is motivated by the lack of effective treatment options for metastatic tumors refractory to the current standard of care. It describes methods for synthesizing novel immunogenic complexes (microbial mimetics) designed to prevent or treat metastatic cancer, by harnessing the immune system's natural ability to eliminate microbial infected cells, which harbor the antigenic targets of activated T cells. In the context of microbial mimetics (MM), either tumor-specific or tumor-associated antigens may be referred to as “antigenic cargo” or “antigenic targets”.